Brain Metabolite Changes In Cortical Gray And Normal-Appearing White Matter In Clinically Early Relapsing/Remitting Multiple Sclerosis
Chard DT, Griffin CM, McLean MA, Kapeller P, Kapoor R, Thompson AJ, Miller DH
Brain 2002 Oct;125(Pt 10):2342-52
Institute of Neurology, NMR Research Unit, University College London, Queen Square, London WC1N 3BG, UK
While much work has concentrated on focal White Matter (WM) lesions in Multiple Sclerosis, there is growing evidence to suggest that Normal-Appearing WM (NAWM) and Gray Matter (GM) are also involved in the disease process.
This study investigated Multiple Sclerosis disease effects on NAWM and Cortical GM (CGM) metabolite concentrations, and the relationships between these metabolite concentrations and clinical impairment.
Proton Magnetic Resonance Spectroscopic imaging (1H-MRSI) data acquired using Point Resolved Spectroscopic (PRESS) localization (echo time 30 ms, repetition time 3000 ms, nominal Voxel volume 2.3 ml).
From 27 Relapsing/Remitting Multiple Sclerosis and 29 normal control (NC) subjects were processed using LCModel to estimate metabolite concentrations in millimoles per litre.
1H-MRSI voxel tissue contents were estimated using SPM99 tissue and semi-automatic lesion segmentations of three-dimensional fast spoiled gradient recall scans acquired during the same scanning session.
NAWM and CGM metabolite concentrations estimated were: Choline-containing compounds (Cho); Creatine and PhosphoCreatine (Cr); myo-Inositol (Ins); N-AcetylAspartate plus N-AcetylAspartyl-Glutamate (tNAA); and Glutamate plus Glutamine (Glx).
CGM data came from 24 of the Multiple Sclerosis (mean age 35.2 years, mean disease duration 1.7 years) and 25 of the NC (mean age 34.9 years) subjects.
NAWM data came from 25 of the Multiple Sclerosis (mean age 35.0 years, mean disease duration 1.7 years) and 28 of the NC (mean age 36.7 years) subjects.
Metabolite concentrations were compared between Multiple Sclerosis and NC subjects using multiple (linear) regression models allowing for age, gender, 1H-MRSI voxel tissue and CSF contents, and Brain Parenchymal Volume.
At a significance level of P < 0.05, CGM Cho, CGM and NAWM tNAA, and CGM Glx were all significantly reduced, and NAWM Ins was significantly elevated.
Spearman correlations of Multiple Sclerosis Functional Composite Scores with tissue metabolite concentrations were significant for the following: CGM Cr (r(s) = 0.524, P = 0.009), CGM Glx (r(s) = 0.580, P = 0.003) and NAWM Ins (r(s) = -0.559, P = 0.004).
These results indicate that metabolite changes in NAWM and CGM can be detected early in the clinical course of Multiple Sclerosis, and that some of these changes relate to clinical status.
The correlation of clinical impairment with CGM Cr and Glx but not tNAA suggests that it is more closely associated with Neuronal metabolic dysfunction rather than loss in Clinically Early Relapsing/Remitting Multiple Sclerosis.
The correlation of clinical impairment with a raised NAWM Ins may indicate that Glial proliferation also relates to function at this stage of the disease.
Beneficial Effects Of Acetazolamide On Paroxysmal Attacks Of Girdle Sensation In Multiple Sclerosis
Hamasaki S, Furuya T, Motomura M, Shirabe S, Nakamura T
Rinsho Shinkeigaku 1998 Jul;38(7):697-9
Nagasaki University, School of Medicine, First Department of Internal Medicine, Japan
A 56-year-old woman with a 40-year history of Multiple Sclerosis (MS) developed Paroxysmal attacks of Girdle Sensation in the Th5-6 Dermatomes.
The attacks lasted 20-60 minutes and occured up to three times per week. T2-weighted MR imaging of the Spinal Cord showed high intensity area from Th5 to Th8.
ElEctroCardiography, EchoCardiography and laboratory findings did not indicate Ischemic Heart Disease; therefore, the Paroxysms were attributed to the Spinal Cord lesions. Attacks were successfully suppressed by Acetazolamide 250 mg/day.
Although Carbamazepine is frequently used to treat Paroxysmal attacks in MS, we would like to suggest that Acetazolamide may also be beneficial in some patients with Paroxysmal Symptoms.
Disease-Modifying Therapies For Multiple Sclerosis
Corboy JR, Goodin DS, Frohman EM
Curr Treat Options Neurol 2003 Jan;5(1):35-54
University of Colorado Health Sciences Center, Department of Neurology, 4200 East Ninth Avenue, B183, Denver, CO 80262, USA
Multiple Sclerosis (MS) is likely an AutoImmune Disorder, although this remains unproven. ImmunoTherapeutic treatments have been shown to be helpful, especially in Relapsing forms of the illness.
But the treatments are incomplete, and many patients continue to worsen over time, even with standard therapy. ImmunoTherapies presently available appear to have their greatest effect when used early in the course of the illness.
In Relapsing/Remitting Multiple Sclerosis (RRMS), there is overwhelming Class I data from large clinical trials that supports the use of Interferon-beta-1a (IFN-ß-1a), IFN-ß-1b, and Glatiramer Acetate.
Comparative data are limited, and results published in different trials support the idea that treatment outcomes with the various drugs are more similar than different. Decisions about treatment choice should be tailored to the needs of the individual patient.
With the exception of a small number of patients with Benign MS, all RRMS patients should be treated with one of the Interferons or Glatiramer Acetate.
There are Class I data consistent with the idea that higher dose or more frequent administration of IFN-ß is associated with better clinical outcome and reduced progression of changes on brain MRI scans.
The duration of this effect is not clear, and higher dose with more frequent administration is associated with higher cost, more side effects, and greater production of Interferon AntiBodies.
Interferon AntiBodies possibly reduce efficacy of IFN-ß in RRMS and Secondary/Progressive Multiple Sclerosis (SPMS).
Clinically Isolated Syndromes (CIS) of DeMyelination in the Central Nervous System can be reliably diagnosed, and the risk of further episodes of DeMyelination is consistent with the diagnosis of RRMS stratified by use of Brain MRI scans.
Patients at high risk of developing RRMS after CIS achieve significant benefit after treatment with IFN-ß-1a, and initiation of therapy after CIS should be given strong consideration.
There are no similar data for IFN-ß-1b or Glatiramer Acetate, but logic would dictate a similar response with these agents.
In SPMS, there are Class I data that treatment with IFN-ß-1a or IFN-ß-1b has a significant effect on progression of Brain MRI lesions, but clinical outcomes are less clearly affected.
It is justifiable to treat SPMS patients with IFN-ß. Mitoxantrone may be effective in slowing progression of SPMS, and its risks are moderate. It should be used in patients with SPMS, but potential long-term risks must be discussed with the patient in detail.
Results of treatment of SPMS in advanced cases (Extended Disability Status Score greater than 6.5, or restricted to wheelchair) is mostly unknown.
These patients are at high risk of developing infections, especially if they use indwelling catheters, and the use of agents that induce ImmunoSuppression may be risky.
There are no effective therapies for Primary/Progressive Multiple Sclerosis (PPMS). Although PPMS patients are frequently treated with one or more therapeutic agents, there is no medical justification for this now.
Preservation Of Neurologic Function During Inflammatory DeMyelination Correlates With Axon Sparing In A Mouse Model Of Multiple Sclerosis
Ure DR, Rodriguez M
Mayo Medical and Graduate School, Department of Immunology, 428 Guggenheim Building, 200 1st Street SW, Rochester, MN 55905, USA
Axonal Injury has been proposed as the basis of permanent deficits in the Inflammatory, DeMyelinating Disease, Multiple Sclerosis. However, reports on the degree of injury are highly variable, and the responsible mechanisms are poorly understood.
We examined the relationships among long-term DeMyelination, Inflammation, Axonal Injury, and Motor Function in a model of Multiple Sclerosis, in which mice develop chronic, Immune-mediated DeMyelination of the Spinal Cord resulting from persistent infection with Theiler's Virus.
We studied two strains of mice, inbred SJL/J and C57BL/6x129 mice deficient in ß-2-MicroGlobulin and therefore CD8+ Lymphocytes. After 8 months of disease, SJL mice had considerably worse Motor Function than beta-ß-MicroGlobulin-deficient mice.
Motor Dysfunction correlated linearly with the extent of DeMyelinated lesions in the Spinal Cord (Lesion Load) within each strain, but no difference in lesion load was present between strains. Also, the extent of ReMyelination did not differ between strains.
Instead, the disparity in Motor Deficits reflected differences in the integrity of Descending Neurons. That is, retrograde labeling of ReticuloSpinal, VestibuloSpinal, and RubroSpinal Neurons, although reduced in all chronically diseased mice, was two to seven times higher in ß2-MicroGlobulin-deficient mice.
The labeling was superior in ß2-MicroGlobulin-deficient mice despite the fact that lesion expanse and therefore the number of Axons traversing lesions were similar in both strains.
Thus, by all criteria Axons were equivalently DeMyelinated in SJL and ß-2-MicroGlobulin-deficient mice, but the extent of Axonal Injury differed significantly.
These results indicate that mechanisms of DeMyelination and Axonal Injury are at least partly separable, and are consistent with the hypothesis that CytoToxic CD8+ Lymphocytes may selectively injure DeMyelinated Axons.
Additionally, the data suggest that Axonal injury obligatorily results from chronic Inflammatory DeMyelination and significantly contributes to Neurological Deficits.